Enabling Deoxygenative C(sp2)-C(sp3) Cross-Coupling for Parallel Medicinal Chemistry

Herein we report the developmentof an automated deoxygenativeC-(sp(2))-C-(sp(3)) coupling of aryl bromide withalcohols to enable parallel medicinal chemistry. Alcohols are amongthe most diverse and abundant building blocks, but their usage asalkyl precursors has been limited. Although metallaphotoredox deoxygenativecoupling is becoming a promising strategy to form C-(sp(2))-C-(sp(3)) bond, the reaction setup limits its widespreadapplication in library synthesis. To achieve high throughput and consistency,an automated workflow involving solid-dosing and liquid-handling robotshas been developed. We have successfully demonstrated this high-throughputprotocol is robust and consistent across three automation platforms.Furthermore, guided by cheminformatic analysis, we examined alcoholswith comprehensive chemical space coverage and established a meaningfulscope for medicinal chemistry applications. By accessing the richdiversity of alcohols, this automated protocol has the potential tosubstantially increase the impact of C-(sp(2))-C-(sp(3)) cross-coupling in drug discovery.